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Updated: Aug 12, 2026
A Neonatal Heterotopic Rat Heart Transplantation Model for the Study of Endothelial-to-Mesenchymal Transition
Published on: July 21, 2023
RUNX1-driven endothelial-to-mesenchymal transition contributes to remodelling in LMNA cardiomyopathy
David Wu1,2, Dipti Tripathi1,2,3, Amit Manhas1,4
1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Insights
RUNX1-driven endothelial-to-mesenchymal transition (EndoMT) is a key mechanism in LMNA cardiomyopathy, linking LMNA mutations to fibrosis. Targeting RUNX1 signaling offers a potential therapeutic strategy for fibrotic heart disease.
Area of Science:
- Cardiovascular Biology
- Genetic Cardiology
- Molecular Mechanisms of Disease
Background:
- LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic heart disorder.
- Fibrotic remodeling in LMNA-DCM is poorly understood, despite its association with cardiomyocyte defects.
Purpose of the Study:
- To investigate the mechanisms driving fibrotic remodeling in LMNA-DCM.
- To identify endothelial cell transcriptional and epigenomic states associated with fibrosis.
- To explore RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT) as a therapeutic target.
Main Methods:
- Spatial transcriptomics and single-nuclei multiomics on human LMNA-DCM hearts.
- Utilized patient-specific induced pluripotent stem cell-derived endothelial cells and cardiac organoids.
- Employed the LMNAH222P/H222P mouse model for in vivo studies.
- Investigated genetic and pharmacological RUNX1 inhibition.
Main Results:
- Identified endothelial EndoMT signatures in human LMNA-DCM hearts.
- LMNA deficiency induced endothelial dysfunction and RUNX1 activation.
- RUNX1 inhibition restored endothelial identity and normalized cardiac function in organoids and mice.
- Pharmacological RUNX1 inhibition reduced fibrosis and preserved cardiac function in a mouse model.
Conclusions:
- RUNX1-driven EndoMT is a central mechanism linking LMNA mutations to fibrosis in cardiomyopathy.
- Endothelial transcriptional reprogramming and RUNX1 signaling are potential therapeutic targets for fibrotic cardiomyopathy.
Background And Aims:
LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic disorder characterized by conduction disease, malignant arrhythmias, myocardial fibrosis, and heart failure. Although LMNA mutations have traditionally been associated with cardiomyocyte-intrinsic defects, the mechanisms driving fibrotic remodelling remain incompletely understood.
Methods:
Spatial transcriptomics and integrated single-nuclei multiomics were performed on explanted human LMNA-DCM hearts to define endothelial transcriptional and epigenomic states associated with fibrosis. Patient-specific induced pluripotent stem cell-derived endothelial cells, engineered cardiac organoids, and the LMNAH222P/H222P mouse model were used to investigate RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT). Genetic and pharmacological RUNX1 inhibition strategies were evaluated in vitro and in vivo.
Results:
Endothelial populations exhibiting EndoMT-associated transcriptional and epigenomic signatures were identified in human LMNA-DCM hearts. LMNA induced pluripotent stem cell-derived endothelial cells demonstrated endothelial dysfunction, mesenchymal gene activation, and epigenetic activation of RUNX1 following loss of LMNA-mediated repression. Genetic RUNX1 deletion restored endothelial identity, reversed EndoMT-associated transcriptional programmes, and normalized chromatin accessibility at endothelial regulatory loci. In multicellular cardiac organoids, endothelial RUNX1 activation impaired endothelial-cardiomyocyte signalling and cardiomyocyte contractile function, whereas endothelial-specific RUNX1 deletion restored endothelial and myocardial function. Pharmacological RUNX1 inhibition with Ro24-7429 similarly improved endothelial and cardiomyocyte function in vitro and reduced myocardial fibrosis while preserving cardiac function in LMNAH222P/H222P mice, including after disease onset.
Conclusions:
RUNX1-driven EndoMT represents a central mechanism linking LMNA mutations to fibrotic remodelling in LMNA cardiomyopathy. These findings support endothelial transcriptional reprogramming and RUNX1 signalling as potential therapeutic targets in fibrotic cardiomyopathy.
